1. Field of the Invention
This invention relates to thyroid-hormone receptor binding compounds, and more particularly to thyroid-hormone receptor binding compounds useful as dermatologic treatments for atrophy of the dermis.
2. Brief Description of the Related Art
There are a considerable number of skin conditions and diseases which significantly affect the appearance of the skin. Examples of these skin conditions include stria, cellulite, roughened skin, actinic skin damage, intrinsically aged skin, photodamaged skin, lichen planus, ichtyosis acne, psoriasis, wrinkled skin, eczema, seborrheic dermatitis, scleroderma, hyperkeratinizing disorders, keloids and skin scarring.
A wide variety of medically useful topical skin preparations are currently commercially available to treat many of these skin conditions and diseases. A large number of these skin preparations include topical steroids such as glucocorticoids, and retinoid topical medicaments, both of which have varying side-effects and usefulness in many patients. Particularly, eczema and psoriasis are usually treated with topical steroids such as hydrocortisone, betamethasone, and clobetasol propionate. The side effects of topical steroid use, particularly in the long term are well known and include skin atrophy consisting of atrophy of both the dermis and epidermis, a risk for systemic absorption of the drug, and rebound phenomena when the drug is withdrawn.
Oral glucocorticoids also produce skin atrophy with chronic use. Therefore certain diseases and conditions which are treated with oral or inhaled glucocorticoids are associated with atrophy. For example, organ transplantation, asthma, rheumatic diseases, and renal diseases are often treated with oral glucocorticoids which results in skin atrophy.
Dermal skin atrophy results from reduced collagen in the dermis, decreased cellularity in the dermis, and reduces the depth of the dermis, resulting in increased fragility of the skin, transparency of the skin, and easy bruising (Talwar et al., J. Inv. Derm. 105:285 (1995); Uitto, H. Geriatric Dermatology 5:127 (1989)). Among the main causes of dermal skin atrophy are aging, photodamage, topical or systemic glucocorticoids, Cushing""s disease, rheumatoid arthritis, and diabetes (see, Textbook of Dermatology, (1997); Gilchrist, B. A. Brit. J. Dermatology 135:867 (1996); Talwar et al., J. Inv. Derm. 105:285 (1995)).
Retinoic acid has been shown to partially ameliorate the condition of photoaging (Drugs and Aging 1:12-16 (1996)), but has not been fully successful in reversing steroid induced dermal skin atrophy in humans (Griffiths, Br. J. Dermatology 135:60-64 (1996)). Other medically useful treatments involve the use of alpha hydroxy acids as disclosed in U.S. Pat. Nos. 5,254,343; t,284,971; 5,401,772; 3,649,597; 3,357,887; 4,168,385; and 5,179097; and European Patent Application No. 580550. Currently, there are no treatments for dermal atrophy of the skin that are widely accepted by the medical community or can reverse glucocorticoid-induced dermal atrophy.
The structurally similar thyroid hormone compounds 3,3xe2x80x2,5-triiodo-L-thyronine (T3) and L-thyroxine (T4) have a very wide range of effects. In adult mammals they influence nearly all organs, the metabolism of nutrients, basal metabolic rate, and oxygen consumption. In humans, the deficiency or excess of circulating thyroid hormone compounds results in the well characterized syndromes, hypo- and hyperthyroidism. Small concentrations of thyroid hormone metabolites which are also endocrinologically active exist. Among these compounds are tri-iodothyroacetic acid (xe2x80x9cTriacxe2x80x9d [4-(4-hydroxy-3-iodophenoxy)-3,5-diodophenyl]acetic acid) and tri-iodopropionic acid (xe2x80x9cTri-propxe2x80x9d [4-(4-hydroxy-3-iodophenoxy)-3,5-diiodophenyl)]propionic acid).
Thyroid hormone compounds exert many of their actions by binding to a family of receptor proteins termed the C-erb-A family. In humans, their receptor protein family is now known to comprise several members, notably the human thyroid receptor xcex1-1, the human thyroid receptor xcex1-2 which binds the hormone poorly or not at all, the human thyroid receptor xcex2-1, and the human thyroid receptor xcex2-2. These proteins are part of a larger superfamily of steroid hormone receptors which comprises the glucocorticoid receptors, the retinoic acid receptors, the vitamin D receptors, and the insect molting receptors (e.g., the receptors for ecdysone and the insect juvenile hormones). Receptors for hormone compounds are found in human skin, human fibroblasts and keratinocytes and they are also found in many other tissues within the human body,
In addition to the naturally occurring thyroid hormone compounds (e.g., triiodothyronine and tetraiodothyronine), a large number of chemical compounds which bind to the thyroid hormone receptor and which produce thyroid hormone-like effects have been synthesized (see, for example, U.S. Pat. No. 5,401,772).
Thyroid hormone compounds, in many cases, act indirectly by influencing the effects of other hormones and tissues. For example in the rat, thyroid administration increases pituitary growth hormone production which in turn affects hepatic protein production including that of alpha-2 euglobulin. Functionally, in the rat, growth hormone may act as a second message for thyroid hormone. The biology of thyroid hormone compounds has been extensively studied only after oral administration, which makes the relationship between a direct effect of thyroid hormone compounds and an indirect effect mediated by thyroid hormone modulation of other autocrine, paracrine or endocrine factors difficult to ascertain.
Orally administered thyroid hormones influence the connective tissue biology of the skin. When given orally, thyroid hormones induce an increase in neutral salt and acid soluble collagen, but decrease insoluble collagen in the skin of guinea pigs (Drozdzm, M. et al., Endokrinologie 73:105-111, 1979). In cell culture, fibronectin production is decreased in human fibroblasts and fibroblast glycosaminoglycans are either decreased or unchanged depending on the experimental conditions used (Murata, Y. et al., J. Clin. Endocrinol. Metab. 64:334-339, 1987; Watxke, H. et al., Thrombosis Res. 46:347-353, 1987; Murata, Y. et al., JCEM 57:1233-1239, 1983; Ceccarelli, Pl, et al., JCEM 65:242-246, 1987). Keratin gene expression for both the basal cell keratin K5 and K14 genes and the differentiation-specific K10 gene is negatively regulated by thyroid hormones (Tomic-Canic, M. et al., J. Invest. Dermatol. 99:842-847, 1992; Blumenberg, M. et al., J. Invest. Dermatol. 98:42S-49S, 1992) Thyroid hormone added to fibroblasts in culture decreases collagen production (De Ryker, FEBS Lett. 174:34-37 (1984)). Some of these effects are mirrored by similar cell culture responses to retinoic acid or the retinoid Tretinoin.
Histological studies of skin from individuals who have the medical condition hyperthyroidism show an increased number of cell layers in the skin, reflected by mean epidermal cell number, increased protein turnover with increased proline incorporation and generalized increases in epidermal proliferation compared to normal skin (Holt, P. J. A. et al., Br. J. Dermatol. 95:513-518, 1976). In human clinical biology, thyroid hormone excess leads to a general smoothing of the skin and the loss of wrinkles especially over the olecranon (elbow) surface.
Orally given thyroid hormone compounds in excess of normal bodily requirements or medical conditions which are associated with excess thyroid hormone compounds such as Grave""s disease or toxic nodular goiter produce an acceleration of heart beat with associated heart failure, cardiac arrhythmias, osteoporosis, increased intestinal motility leading to diarrhoea, psychiatric abnormalities, and an increase in the basal metabolic rate. Attempts to use oral thyroid hormone compounds for diminishing lipid levels in man resulted in increased cardiac deaths.
What is needed in the art is a method of treating dermal skin atrophy that does not suffer the drawbacks of current treatment used in the art. The present invention is believed to be an answer to that need.
In one aspect, the present invention is directed to a method for treating dermal atrophy of the skin, comprising the step of applying a composition to the skin of a mammal suffering from dermal atrophy of the skin, the composition comprising at least one thyroid hormone compound or thyroid hormone-like compound together with a pharmacologically acceptable base suitable for topical application, wherein the thyroid hormone compound or the thyroid hormone-like compound binds to TR-xcex1 or TR-xcex2 with an equilibrium dissociation constant, Kd, of at least 10xe2x88x925 M, wherein Kd=(R)xe2x80xa2(L)/(RL), where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex, and wherein the dermal atrophy of the skin is reduced.
In another aspect, the present invention is directed to an article of manufacture comprising packaging material and a pharmaceutical agent contained within the packaging material, wherein the pharmaceutical agent is therapeutically effective for treating dermal atrophy of the skin, and wherein the packaging material comprises a label which indicates that the pharmaceutical agent can be used for treating dermal atrophy of the skin, and wherein the pharmaceutical agent comprises at least one thyroid hormone compound or thyroid hormone-like compound in a pharmacologically acceptable base suitable for topical application, wherein the thyroid hormone compound or the thyroid hormone-like compound binds to TR-xcex1 or TR-xcex2 with an equilibrium dissociation constant, Kd, of at least 10xe2x88x925 M wherein Kd=(R)xe2x80xa2(L)/(RL), where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex.
In yet another aspect, the present invention is directed to a composition for treating dermal atrophy of the skin, comprising: at least one thyroid hormone compound or thyroid hormone-like compound selected from the group consisting of tri-iodothyroacetic acid, tri-iodopropionic acid, 4-[2,6-dibromo-4-(1H-tetrazol-5-ylmethyl)-phenoxyl-2-isopropyl-phenol, 4-(4-hydroxymehyl-2,6-diiodophenoxy)-2-iodo-phenol, and combinations thereof; and a pharmacologically acceptable base comprising oil in water emulsions, water in oil emulsions, sprays, liposomes, creams, lotions, solutions, and combinations thereof.
In yet another aspect, the present invention is directed to a method of improving healing of wounded skin of a patient, comprising the step of applying a composition to the wounded skin of the patient, the composition comprising at least one thyroid hormone compound or thyroid hormone-like compound together with a pharmacologically acceptable base suitable for topical application, wherein the thyroid hormone compound or the thyroid hormone-like compound binds to TR-xcex1 or TR-xcex2 with an equilibrium dissociation constant, Kd, of at least 10xe2x88x925 M, wherein Kd=(R)xe2x80xa2(L)/(RL), where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex, and wherein the healing of the wounded skin is improved.
In another aspect, the present invention is directed to a method of dermatological surgical pretreatment of a patient with atrophied skin, comprising the step of applying a composition to the atrophied skin of the patient prior to dermatological surgery, the composition comprising at least one thyroid hormone compound or thyroid hormone- like compound together with a pharmacologically acceptable base suitable for topical application, wherein the thyroid hormone compound or the thyroid hormone-like compound binds to TR-xcex1 or TR-xcex2 with an equilibrium dissociation constant, Kd, of at least 10xe2x88x925 M, wherein Kd=(R)xe2x80xa2(L)/(RL), where (R) is the concentration of receptor, (L) is the concentration of ligand, and (RL) is the concentration of the receptor-ligand complex.
These and other aspects will become apparent from the following drawings and detailed description.